Neuroleptic drugs, including haloperidol, thioridazine, chlorpromazine, flupenazine and thiothixene, are used as antipsychotics to treat a number of psychoses, such as schizophrenia, schizoaffective disorder, organic psychosis, bipolar disorder, and unipolar depression (severe form). This represents a sizable portion of Americans, as the National Institute of Mental Health reports that the number of patients in the United States with schizophrenia in 1990 was 1.8 million; bi-polar disorder, 1.1 million and unipolar depressives (severe form), 1.7 million. Neuroleptics are also used as behavioral control measures in the following non-psychotic populations; children with autism, child and adolescent psychiatric patients with conduct and adjustment disorders, the mentally retarded, and geriatric patients in general hospitals and nursing homes. In these populations, clinical trials have established that these agents are effective in the treatment of symptoms such as; tension, hyperactivity, combativeness, hostility, negativism, hallucinations, acute delusions, poor self-care, and sometimes withdrawal and seclusiveness. Neuroleptics are also the drug of choice to treat the symptoms of abnormal movements in primary neurological disorders; such as for patients with tic disorders (transient tic disorders, chronic motor tics, Tourettes' disorder) and those with Huntington's Disorder.
Unfortunately, in a large number of individuals, a variety of movement disorders may develop secondary to chronic neuroleptic treatment thereby creating a therapeutic dilemma in the mental health community. Among these disorders are tardive dyskinesia (TD), Parkinsonism, tardive dystonia, akathisia and neuroleptic malignant syndrome.
A similar class of drugs, as represented by the drug methochlorpromide, used as anti-vomiting agents (particularly for cancer chemotherapy patients) are also known to cause a similar set of movement disorders. Additionally, a variety of movement disorders are seen secondary to other drugs such as lithium (used for the treatment of bipolar disorder), anticonvulsants (used for the treatment of seizure disorders), benzodiazepines (used for the treatment of anxiety disorders), and tricyclic antidepressants (used for the treatment of unipolar depression).
Abnormal movements are also seen as primary neurological disorders. In addition to the two such conditions mentioned above, tic disorders and Huntington's Disorder, there are many other neurological disorders that are manifested by abnormal movements; these include, myoclonic syndromes, childhood and adult onset dystonias, Wilson's disease, Sydenham's chorea, and other choreas. Several dementias also manifest an abnormal movement component; these include, Alzheimer's disease, Creutzfeldt-Jakob disease, Pick's Disease and Hallervorden Spatz Disease.
The present invention relates to the treatment of abnormal movement disorders, including those mentioned in the sections above, whether they are secondary to drug treatment or primary disorders.
These abnormal movement disorders result in a wide variety of symptoms which can range from unconscious movements which interfere very little with quality of life, to quite severe and disabling movements. Examples of symptoms which are seen secondary to neuroleptic treatment are; involuntary tongue protrusions, snake-like tongue movements, repetitive toe and finger movements, tremors of extremities or whole body sections, muscular rigidity, slowness of movement, facial spasms, acute contractions of various muscles, particularly of the neck and shoulder which may eventually lead to painful, prolonged muscle contraction, restlessness, distress and an inability to remain still.
Thus, while patients suffering from psychoses such as schizophrenia need treatment with neuroleptics to control their psychoses, it can be difficult to integrate these patients back into the mainstream because the movement disorder side effects of their neuroleptic treatment produce a visual stigma, a stigma which is a barrier to complete acceptance of these patients in the world beyond a hospital or a halfway house.
Consequently, even though neuroleptic treatment may offer the best means of effectively treating patients who suffer from various psychoses, a pervasive fear that one or more of these abnormal movement disorders will develop and persist exists among psychiatric patients, their families and their psychiatrists. This fear results in a psychological cap on the therapeutic potential of these neuroleptic drugs to treat psychosis. It should be noted that the development of TD has been the cause of malpractice suits brought against psychiatrists.
One means of removing this barrier to continued and necessary treatment with neuroleptics has been the development of atypical neuroleptic drugs (one of which, clozapine, is available in the U.S.). These drugs are less likely to result in movement disorder side-effects. However, clozapine has some disadvantages relevant to our concerns; it was developed too late to help some patients, carries the risk of other serious life-threatening side effects which require expensive monitoring, and thus is not appropriate to all. For instance, some public mental health facilities, because of cost issues, must necessarily limit the use of this drug to only a small segment of the population that they treat.
The present inventor has conducted a 15 year course of study in neuroleptic-induced abnormal movement disorders. This work is represented by the work she has done to define the etiology, pathophysiology, and to develop treatment and preventive strategies for one of the neuroleptic-induced movement disorders, TD. The research strategy in this facet of her work was to define risk factors for the development of this disorder in all the major neuroleptic treated populations (adult psychiatric patients, geriatric psychiatric patients, child psychiatric patients and the mentally retarded), to search for commonalities in these risk factors across populations and then to integrate these findings into a unitary biochemical paradigm for the pathophysiology of TD. The unitary paradigm that was generated from the data of these studies defines the metabolism of the large neutral amino acid, phenylalanine, as a pathophysiologic element in TD. The individual study findings that most directly led to this paradigm were those of a large scale point prevalence study of TD among mentally retarded (not psychotic) residents (n=211) of a state developmental center (Study one-see below). In that study the inherited metabolic disorder phenylketonuria (PKU) was found to be a strong and statistically significant risk factor for TD development. The power of that risk factor was demonstrated by the fact that eighty-six percent of the phenylketonurics in the sample had TD as compared to a rate of only 27% of the non-PKU population. This study is seminal in the field of neuroleptic-induced movement disorder research in that it was the first reported association of a medical condition (metabolic neurological disorder) with TD and thus provided a new direction for further research. That direction was the search in the well characterized pathophysiology of PKU for a clue to the pathophysiology of TD. It is well known that PKU is an inherited metabolic disease (carried on chromosome 12) in which the activity of phenylalanine hydroxylase, the enzyme responsible for conversion of the large neutral amino acid phenylalanine to tyrosine, is absent or drastically reduced. This deficit creates a condition in which there is a chronic excess of phenylalanine in the plasma and thus in the brain of PKU patients (Richardson, et al , "The prevalence of tardive dyskinesia in a mentally retarded population," Psychopharmacol. Bull., 22:243-249, 1986; Scriver, C. R., Kaufman, S. and Woo, S. L. C., "The hyperphenylalaninemias," The Metabolic Basis of Inherited Disease, edited by Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D. New York, N.Y., McGraw Hill, 1989, pp. 495-546).
Given this clue and in the search for a unitary hypothesis across populations, the present inventor undertook a study to test whether the metabolic response of phenylalanine metabolism to a dietary challenge (protein load) differentiated male schizophrenic patients (the heaviest users of neuroleptics) with TD from those without the disorder and further, whether the metabolic response of the TD patients could be characterized as PKU-like (Study Two--see below). This means whether schizophrenic patients with TD would show significantly higher levels of phenylalanine after the challenge. This was in fact the case with the finding of significantly higher post challenge levels of phenylalanine and the phenylalanine/large neutral amino acid ratio (LNAA) or a PKU-like response in patients with TD (Richardson, et al., "The plasma phenylalanine/large neutral amino acid ratio: a risk factor for tardive dyskinesia," psychopharmacol. Bull. 25:47-51 (1989); "Amino acid metabolism and tardive dyskinesia vulnerability in schizophrenia", Biological Psychiatry, 2, 341-343 (Excerpta medica, 1991).
A large scale replication (Study Three; n=209 males; n=103 females) of Study Two found that the metabolic response to a phenylalanine challenge (100 mg/kg) dramatically and significantly distinguished males with TD from those without the disorder, thus establishing phenylalanine metabolism as a pathophysiological element in TD.
Berry, et al. (U.S. Pat. Nos. 4,252,822 and 4,209,531, and "PRELIMINARY SUPPORT FOR THE ORAL ADMINISTRATION OF VALINE, ISOLEUCINE AND LEUCINE FOR PHENYLKETOURIA," Developmental Medicine and child Neurology, 27:33-39 (1985) and "REDUCTION OF CEREBRAL SPINAL FLUID PHENYLALANINE AFTER ORAL ADMINISTRATION OF VALINE, ISOLEUCINE, AND LEUCINE," Pediatric Research, 16:751-755 (1982)) sought specifically to treat the behavioral, perceptual and cognitive symptoms of PKU with the branched chain large neutral amino acids, specifically isoleucine, leucine and valine (BCAA). The behavioral symptoms, some of which are motor in nature, are those of hyperactivity, irritability, poor impulse control, distractibility, aggressivity, and the stereotypical behaviors that are commonly seen in the mentally retarded such as rocking, jumping, running, spinning, flaying, etc. These investigators found that these agents (BCAA) were in fact effective in ameliorating many of the behavioral and cognitive target deficits and with a wider safety margin than with the routine treatment which consisted solely of a diet low in phenylalanine. In two separate studies, Berry, et al., literature supra. administered BCAA to PKU patients; in the first (two cases) they found that the cerebrospinal fluid serum ratio of phenylalanine was reduced and was accompanied by improvements in cognitive function (i.e., motor coordination and task learning). Cognitive improvement was also noted in the second study in three patients who had been treated with a phenylalanine restricted diet as infants and who had nearly normal IQs. The authors specifically found improvements in abstract reasoning and tactile-motor problems and coordination, thereby confirming that these cognitive tasks are particularly sensitive to the biochemical status of PKU patients. Although the behavioral problems improved by Berry, et al. can involve exaggerated movement, such as running, jumping and flaying movements; these are sharply distinguished medically from the abnormal movement disorders, primarily considered to be basal ganglia disease, which are the objectives to be treated herein. Prior to the present inventor's research, the role of phenylalanine in abnormal movement disorders seen secondary to neuroleptic treatment, such as TD, was unknown.
In addition to the work in PKU by Berry, et al., the BCAA as inhibitors of the uptake of aromatic amino acids at the blood-brain barrier neutral amino acid transport system, are used as therapy for several other neurological conditions Adibi, et al , "Branched Chain Amino and Keto Acids in Health and Disease," Basil:Karger (1984).
In one of these, hepatic encephalopathy, BCAA treatment is used successfully to decrease brain transport of the aromatic amino acids (phenylalanine, tyrosine and tryptophan) and of methionine. Two other disorders, maple syrup urine disease and isovaleric acidemia, whose pathology involves inability to catabolize the BCAA and thus cause excess levels of plasma BCAA, are treated by dietary alteration of plasma BCAA levels. Symptoms of maple syrup urine disease are neurological and include movement disorders (i.e., rigidity) and severe mental retardation. Therapy with a diet low in BCAA has been effective only if started immediately after birth.
In addition to the therapeutic use of the branched chain large neutral amino acids in the disorders mentioned above, the aromatic large neutral amino acid, tryptophan has been shown to impact in a complex manner on the symptoms of abnormal movement disorders. For instance, for the myoclonic syndromes and Tourette's disorder there are reports that both augmenting and depressing tryptophan supply to the brain can reduce symptoms (Van Woert, et al., Monographs in Neural Sciences, 3, 71-80, (1976); Avanzini, et al., Monographs in Neural Sciences, 5, 142-152 (1980); Jacobs, et al., Gilles de la Tourette Syndrome, eds. Friedhoff, A. J. and Chase, T. N., pp. 93-97, New York: Raven Press (1982)). This complexity and a further lack of replication has also been seen in the use of tryptophan for the modulation of TD symptoms. Two case reports showed a reduction of TD symptoms following administration of L-Tryptophan to a patient who was receiving the agent for insomnia; the finding was repeated in a second patient also being treated for insomnia (Sandyk, R., Consroe, P. F., Iacono, R. P., " L-tryptophan in drug-induced movement disorders with insomnia," N. Engl. J. Med. 1986, 314(19):1257; Sandyk, R., Bamford, C. R., Khan, I. Fisher, H., "L-tryptophan in neuroleptic-induced tardive dyskinesia," Int. J. Neurosci., 1988, 42:127-130). However, earlier work with seven patients reported no change in TD with concomitant administration of 5-hydroxytryptophan and carbidopa (Nasrallah, H. A., Smith, R. E., Dunner, F. J., McCalley-Whitters, M., "Serotonin precursor effects in tardive dyskinesia," Pharmacology, 1982, 77:234-235) or in 4 patients with the administration of D-L tryptophan (Jus, K., Jus A., Gautier, J. Villeneuve, A. Pires, P. Pineau, R., Villeneuve, R., "Studies on the action of certain pharmacological agents on tardive dyskinesia and on the rabbit syndrome," Int. J. Clin. Pharmacol. 1974, 9(2):138-145).